Basal Ganglia Pathways for Stopping and Switching

基底神经节通路的停止和切换

• 批准号: 8743281
• 负责人: JOSHUA D BERKE
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743281
• 关键词: Accounting; Acetylcholine; Affect; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Behavioral; Behavioral inhibition; Brain; Cell Nucleus; Cells; Clinical; Cognitive; Corpus striatum structure; Cues; Data; Disease; Dopamine; Drug Addiction; Electrophysiology (science); Equus caballus; Event; Failure; Generations; Gilles de la Tourette syndrome; Goals; Human; Individual; Investigation; Learning; Life; Measurement; Mental disorders; Methods; Modeling; Monitor; Motor; Motor output; Movement; Neuromodulator; Neurons; Obesity; Optics; Output; Pathway interactions; Performance; Physiologic pulse; Population; Preparation; Process; Race; Rattus; Reaction; Relative (related person); Resolution; Role; STN stimulation; Self-control as a personality trait; Series; Services; Signal Transduction; Stimulus; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Techniques; Testing; Thalamic structure; Time; cognitive control; design; drug abuser; flexibility; frontal lobe; improved; innovation; insight; neurochemistry; neuromechanism; neuroregulation; novel; optogenetics; public health relevance; relating to nervous system; research study; response; theories; tool

DESCRIPTION (provided by applicant): Behavioral inhibition is central to self-control. Daily life is made immeasurably easier by a repertoire of learned responses to stimuli, yet we need to interrupt and override such responses as circumstances and goals change. Problems with inhibitory function characterize a range of psychiatric disorders including drug addiction, attention-deficit hyperactivity disorder, and Tourette Syndrome. Despite the importance of behavioral inhibition, our understanding of the neural mechanisms involved remains very limited. A standard tool to probe behavioral inhibition is the Stop-signal task. Subjects are signaled to make quick actions, and in a subset of trials are later instructed to cancel those movements before they begin. It has long been hypothesized that Stop-signal performance reflects a race between Go and Stop processes, but how this race corresponds to brain activity is not clear. Although there is a great deal of evidence that deep brain structures called the basal ganglia are involved in stopping, there has been little corresponding investigation of the basal ganglia using the method with the best temporal resolution - electrophysiology of single neurons. We have recently found evidence for a neural race between distinct basal ganglia pathways. Activity in sensorimotor striatum (STR) appeared to correspond to a Go process, while Stop cues instead provoked very fast responses in the subthalamic nucleus (STN). Both of these areas project to the substantia nigra pars reticulata (SNr), which can operate as a gateway to motor output. The relative timing of STR and STN firing determined whether SNr cells responded to the Stop cue (observed when inhibition was successful), or not (when inhibition failed). However, our data also suggest that the STN-SNr pathway actually provides a fast yet transient movement pause, with complete cancellation requiring a separate suppression of STR output. We hypothesize that these two mechanisms serve complementary functions, allowing behavioral inhibition to be both fast and selective. To investigate these processes further, we propose a series of experiments using state-of-the-art techniques for monitoring and manipulating the basal ganglia. For Aim 1 we will compare Stop-related activity in distinct subregions within STR, STN and SNr, to better define how information flows through "motor" and "cognitive" circuits. For Aim 2 we will investigate whether STN signals are specific to stopping, and whether they are driven by the intralaminar thalamus, an area involved in fast orienting reactions. For Aim 3 we will use selective optogenetic suppression and stimulation of the STN-SNr pathway to confirm that it provides a fast motor pause. Finally, for Aim 4 we will explore how the key neuromodulators acetylcholine and dopamine contribute to the suppression of STR output during successfully cancelled actions. Overall, this project would break new ground in determining with unprecedented precision how we are able to rapidly suppress unwanted or inappropriate actions, in the service of adaptive, flexible behavior.

描述（由申请人提供）：行为抑制是自我控制的核心。对刺激的一系列习得性反应使日常生活变得无比简单，但随着环境和目标的变化，我们需要打断和推翻这些反应。抑制功能的问题表征了一系列精神障碍，包括药物成瘾、注意力缺陷多动障碍和抽动秽语综合征。尽管行为抑制的重要性，我们的理解所涉及的神经机制仍然非常有限。 探测行为抑制的标准工具是停止信号任务。受试者被告知要做出快速的动作，并且在试验的一个子集中，随后被指示在这些动作开始之前取消这些动作。长期以来，人们一直假设停止信号的表现反映了Go和Stop过程之间的竞争，但这种竞争如何对应于大脑活动尚不清楚。虽然有大量的证据表明，称为基底神经节的脑深部结构参与停止，但很少有相应的研究基底神经节使用最佳时间分辨率的方法-单神经元电生理学。 我们最近发现了不同基底神经节通路之间的神经竞赛的证据。感觉运动纹状体（STR）的活动似乎与Go过程相对应，而停止提示则在丘脑底核（STN）中引起非常快速的反应。这两个区域都投射到黑质网状部（SNr），它可以作为运动输出的门户。STR和STR触发的相对时间决定了SNr细胞是否对停止提示做出反应（当抑制成功时观察到），或者没有反应（当抑制失败时）。 然而，我们的数据还表明，STN-SNr通路实际上提供了一个快速而短暂的运动暂停，完全取消需要单独抑制STR输出。我们假设这两种机制具有互补的功能，使行为抑制既快速又有选择性。为了进一步研究这些过程，我们提出了一系列实验，使用最先进的技术来监测和操纵基底神经节。对于目标1，我们将比较STR、SNR和SNr中不同子区域的停止相关活动，以更好地定义信息如何通过“运动”和“认知”回路流动。对于目标2，我们将研究是否有特定的停止信号，以及它们是否由板内丘脑驱动，这是一个参与快速定向反应的区域。对于目标3，我们将使用STN-SNr通路的选择性光遗传学抑制和刺激来确认其提供快速运动暂停。最后，对于目标4，我们将探讨关键的神经调节剂乙酰胆碱和多巴胺如何在成功取消动作期间抑制STR输出。 总的来说，这个项目将以前所未有的精度确定我们如何能够快速抑制不想要的或不适当的行为，以适应性，灵活的行为。